Acute inflammation is a protective response that combats invading organisms and repairs tissue injury (Majno & kris, Cells, tissues, and disease: principles of general pathology (Oxford University Press, New York) 2nd Ed pp xxviii, 1005 (2004)). Ideally this response is self-limited and leads to clearance of pathogens, cellular debris and inflammatory mediators, and allows tissues to return to homeostasis (Majno and Medzhitov, Cell 140:771-776 (2010)). However, an excessive inflammatory response impairs resolution and leads to chronic inflammation and subsequent tissue damage (Majno, et al. FASEB J 21(2):325-332 (2007); Lawrence & Gilroy, Int. J. Exp. Pathol. 88:85-94(2007). Increasing evidence suggests that excessive inflammation and impaired resolution play central roles in several prevalent diseases including cardiovascular, metabolic, and neurodegenerative diseases (Nathan & Ding, Cell 140:871-882 (2010)). Hence, development of therapeutics that temper inflammation and enhance resolution are of considerable interest.
Advances in vascular biology have revealed a pivotal role of inflammation in the pathophysiology of atherosclerosis, the major cause of cardiovascular diseases and the leading cause of morbidity and mortality in developed world (Hansson, N Engl J Med 352(16):1685-1695 (2005); Libby et al Nature 473(7347):317-325 (2011)). Atherosclerotic plaques develop through a maladaptive, macrophage-driven, chronic inflammatory response to subendothelial lipoproteins with defective inflammation resolution (Tabas, Nat Rev Immunol 10(1):36-46 (2010)). This defective resolution of inflammation results in an increased permeation of lipoproteins and adhesion molecules, followed by the recruitment of monocytes that differentiate into macrophages and eventually transform into lipid-laden foam cells beneath the endothelium. Through apoptosis and failure of efferocytosis, which is a specific and important component of the resolution response, these foam cells undergo secondary necrosis, leading to the formation of the necrotic core in atherosclerotic lesions. This atherogenic inflammatory cycle promotes the progression of atherosclerotic lesions into dangerous plaques that are vulnerable to rupture, which can in turn trigger acute, obstructive vascular thrombosis, myocardial infarctions, and most strokes (Libby, Nature 420(6917):868-874 (2002)). The knowledge of inflammatory cascade involved offers new opportunities for the treatment and prevention of atherosclerosis, among which nanoparticles (NPs) containing anti-inflammatory and pro-resolving agents present an attractive nanomedicine approach.
Atherosclerotic plaques develop through a maladaptive, macrophage-driven chronic inflammatory response to subendothelial lipoproteins. Macrophages are a key cell type in this inflammatory response and thus have thus emerged as a key imaging and therapeutic target for atherosclerosis.
Although a number of promising arterial-wall targets have been identified and validated using molecular-genetic approaches in animal models of atherosclerosis, many of these are not amenable to systemic or oral delivery due to the nature of the compounds (e.g., proteins), lack of efficient delivery to plaques, safety concerns related to delivery to the liver and other sites; pharmacokinetic issues (e.g. rapid drug clearance).
Resolution of inflammation is now considered to be a distinct process from anti-inflammatory processes. This is because in addition to serving as agonists to stop and lower neutrophil infiltration to inflamed tissues, pro-resolution molecules promote uptake and clearance of apoptotic cells as well as microbes by macrophages in inflamed sites' Resolution is accompanied by an active switch in the mediators that predominate in exudates. The initial mediators generated include prostaglandins and leukotrienes. Next, prostaglandin E2 and D2 gradually induce the production of mediators that have both anti-inflammatory and pro-resolution activities (collectively, pro-resolving lipid mediators (SPMs) such as lipoxions, resolvins, and protectins (reviewed in Serhan, et al Nat Rev Immunol 8(5):349-361 (2008)). Other examples of SPMs include maresins, and specific peptide mediators such as annexin A1 (Serhan, et al. Nat Rev Immunol 9(1):62-70 (2009)). These families of endogenous pro-resolution molecules are not immunosuppressive, but instead, function in resolution by activating specific mechanisms to promote homeostatis Serhan, et al Nat Rev Immunol 8(5):349-361 (2008)).
Bannenberg et al introduced and defined quantitative resolution indices in vivo that allow for temporal regulation of leukocyte trafficking and chemical mediators within inflammatory exudates (Bannenberg, et al. J Immunol 174(7):4345-4355 (2005)). These indices are the maximal neutrophil numbers that are present in the exudates (ψmax); the time when ψmax occurs (Tmax); and the resolution interval from Tmax to T50 (Ri), i.e., the time it takes for the number of poly-morphonuclear neutrophils (PMNs) to reach half ψmax. Importantly, these indices not only provide a quantitative measure of the specific actions of endogenous SPMs and peptides but also provide a means to investigate whether pharmacologic agents can enhance or impair resolution (Bannenberg, et al. Nature 447(7146):869-874 (2007)). In this regard, only a few widely used therapeutics have been assessed for their impact in programmed resolution (Schwab, et al. J Immunol 184(3):1516-1525 (2010)).
The resolution of inflammation is a highly complex process that can involve a balance of pro- and anti-inflammatory mediators (Serhan 2008; Bannenberg et al. J Immunol 174(7):4345-4355 (2005); Fredman, et al Sci Rep 2:639 (2012)). Therapeutics can impair or enhance resolution. For example, cyoclooxygenase and lipoxygenase inhibitors (Schwab, et al., Nature, 447(4176):869-74 (2007)) and lidocaine (Chiang, et al. PLoS One 3(4):e1879 (2008)) impair resolution. Most notable resolution “toxic” drugs are the COX-2 inhibitors that can block the production of PGE2 and PGD2, two critical mediators which initiate resolution (Levy, et al., Nat Immunol 2(7):612-619 (2001)). Aspirin and glucoroticoids can enhance resolution via the generation of aspirin-triggered SPMs (Serhan 2007) or by the endogenous production of annexin-A1, respectively (Perretti & Dalli, Br J Pharmacol 158(4):936-946 (2009)). SPMs and annexin-A1 can bind specific receptors and serve as agonists that trigger protective mechanisms and promote the return to homeostasis (Perretti 2009; Serhan 2008). An ideal therapeutic is one that tempers excessive inflammation and enhances resolution.
Many diseases and disorders involve inflammation. Inflammation may be beneficial, in the case of infection, or damaging, as in cardiovascular disorders, autoimmune disorders, scarring, allergic reactions, chronic lung disorders, ischemia (stroke, traumatic brain injury), to name only a few.
It is therefore an object of the present invention to provide a method and compositions for treatment inflammation.
It is a further object of the present invention to provide a method and compositions for more selective treatment of inflammation, including cardiovascular or ischemic inflammatory disorders.